Patent EA-004180-B1 (EA)
Title: Heteroaryl aminoguanidines and alkoxyguanidines and their use as protease inhibitors
Inventor: LU TIANBAO
IPC: A61P7/02
Filed: 1998-11-25
Abstract: 1. A compound of Formula VII: or a solvate, hydrate or pharmaceutically acceptable salt thereof, wherein R<1> is optionally substituted with C6-10aryl or heterocycle selected from the group consisting of thienyl, pyridine, quinolinyl and imidazolyl, wherein each of them can be substituted; Z is -SO2 or -O(C=O)-; Het is a group where R<3>, R<4> and R<5> are independently hydrogen, C1-12alkyl, C3-7cycloalkyl, C2-6alkenyl, C2-6 alkynyl, optionally substituted C6-10aryl, optionally substituted C6-10ar(C1-4)alkyl, optionally substituted hetero(C6-10)aryl, trifluoromethyl, halogen, hydroxyalkyl, cyano, nitro, carboxaimido, carboxymethyl, alkoxycarbonylmethyl, -CO2R<X>, -CH2OR<X> or -OR<X>, wherein R<X>, in each instance, is independently one of the following group: hydrogen, C1-4alkyl or C3-7cycloalkyl, wherein said alkyl or cycloalkyl groups may optionally have one or more unsaturations; R<7> is hydrogen; R<8> is hydrogen, C1-12alkyl, C6-10ar(C1-6)alkyl or alkoxycarbonyl; R<12> and R<13> are independently hydrogen or C1-12alkyl; or R<12> and R<13> are taken together to form -(CH2)y-, where y is 2 to 7, while R<14> and R<15> are defined above; R<14> and R<15> are hydrogen; X is oxygen; R<A>, R<B> and R<C> are independently hydrogen, C1-12alkyl or alkoxycarbonyl; n and m is from zero to 6. 2. A compound of claim 1, wherein R<1> is C6-10ar(C1-4)alkyl, C6-10aryl, any of which can be optionally substituted; 3. A compound of claim 2, wherein R<1> is C6-10ar(C1-4)alkyl, C6-10aryl, any of which can be optionally substituted by 1-5 of hydroxy, nitro, trifluoromethyl, halogen, C1-6alkyl. 4. A compound of claim 1, wherein Het is selected from the group consisting of where R<3>, R<4> and R<5> are independently hydrogen, C1-4alkyl, C3-7cycloalkyl, C6-10aryl, C6-10 ar(C1-4)alkyl, trifluoromethyl, halogen, hydroxyalkyl, cyano, nitro, carboxamide, carboxy, alkoxycarbonyl, carboxymethyl, alkoxycarbonylmethyl, or cycloalkyloxycarbonyl. 5. A compound of claim 4, wherein R<3>, R<4>, R<5> are independently hydrogen, methyl, ethyl, propyl, chloro, bromo, trifluoromethyl, hydroxymethyl, methoxy, ethoxy, carboxamide, nitro, phenyl, cyclopropyl, hydroxy, isopropyl, methoxycarbonyl, ethoxycarbonyl and benzyl. 6. A compound of claim 1, wherein R<3> and R<4> groups are independently hydrogen, C1-12alkyl, or C2-6alkenyl. 7. A compound of claim 6, wherein R<3> and R<4> are hydrogen. 8. A compound of claim 1, wherein R<5> is hydrogen, halogen, C1-5alkyl, C3-6alkenyl, C3-5cycloalkyl, trifluoromethyl or C1-4alkoxy. 9. A compound of claim 1, wherein Het is: R<3> and R<4> are independently selected from hydrogen or methyl, and R<5> is selected from the group consisting of hydrogen, methyl, ethyl, propenyl, allyl, propyl, isopropyl, butyl, R-sec-butyl, S-sec-butyl, isobutyl, 1-pentyl, R-2-pentyl, S-2-pentyl, 3-pentyl, S-1-(2-methyl)butyl, R-2-(3-methyl)butyl, 1-(3-methyl)butyl, R-1-(2-methyl)butyl, cyclopentyl, 2-pyrolyl, 3-pyrolyl, 1-hexyl, S-2-hexyl, R-2-hexyl, R-3-hexyl, and S-3-hexyl. 10. A compound of claim 9, wherein R<5> is hydrogen, methyl, ethyl, propyl or isopropyl. 11. A compound of claim 1, wherein R<1> is C6-10ar(C1-4)alkyl, C6-10aryl, any of which optionally substituted by 1-5 of: hydroxy, nitro, trifluoromethyl, halogen, C1-6alkyl, C6-10aryl, C1-6alkoxy, C6-10ar(C1-6)alkoxy, C1-6aminoalkyl, C1-6aminoalkoxy, amino, mono(C1-4)alkylamino, di(C1-4)alkylamino, C2-6alkoxycarbonylamino, C2-6alkoxycarbonyl, carboxy, C1-6hydroxyalkyl, C2-6hydroxyalkoxy, (C1-6)alkoxy(C2-6) alkoxy, mono- and diC1-4alkylamino(C2-6)alkoxy, C2-10mono(carboxyalkyl)amino, bis(C2-10carboxyalkyl)amino, C6-14ar(C1-6)alkoxycarbonyl, C2-6-alkynylcarbonyl, C1-6alkynylsulfonyl, C2-6alkenylsulfonyl, C2-6alkynylsulfonyl, C6-10arylsulfonyl, C6-10ar(C1-6)alkylsulfonyl, C1-6alkylsulfinyl, C6-10alkylsulfonamido, C6-10arylsulfonamido, C6-10ar(C1-6)alkylsulfonamido, amidino, guanidino, C1-6alkyliminoamino, formyliminoamino, C2-6carboxyalkoxy, C2-6carboxyalkyl, carboxyalkylamino, cyano, trifluoromethoxy or perfluoroethoxy; Het is: wherein R<3> and R<4> are independently selected from hydrogen or methyl, and R<5> is selected from the group consisting of hydrogen, methyl, ethyl, propenyl, allyl, propyl, isopropyl, butyl, R-sec-butyl, S-sec-butyl, isobutyl, 1-pentyl, R-2-pentyl, S-2-pentyl, 3-pentyl, S-1-(2-methyl)butyl, R-2-(3-methyl)butyl, 1-(3-methyl)butyl, R-1-(2-methyl)butyl, cyclopentyl, 2-pyrolyl, 3-pyrolyl, 1-hexyl, S-2-hexyl, R-2-hexyl, R-3-hexyl, and S-3-hexyl; Z is -SO2-; R<12>, R<13>, R<14> and R<15> are independently hydrogen; X is oxygen; R<A>, R<B> and R<C> are hydrogen; n is zero to 6, and m is zero to 4. 12. A compound of claim 1, wherein Z is -SO2-, R<1> is substituted or unsubstituted C6-10aryl or C6-10alkyl, Het is X is O, R<8> is hydrogen, and R<A>, R<B> and R<C> are all hydrogen. 13. A compound of claim 12, wherein R<1> is substituted or unsubstituted benzyl or phenyl. 14. A compound having Formula VIII: or a solvate, hydrate or pharmaceutically acceptable salt thereof, wherein Z' is -SO2- or -O(C=O); R<21> is optionally substituted C6-10aryl or heterocycle selected from the group consisting of thienyl, pyridine, quinolinyl and imidazolyl; R<25> is hydrogen, C1-4alkyl; C3-7cycloalkyl and trifluoromethyl; R<A>, R<B> and R<C> are independently hydrogen; R<32>, R<33>, R<34> are independently one of hydrogen or C1-12alkyl; or R<32> and R<33> are taken together to form -(CH2)y-, where y is 2 to 5, while R<34> and R<35> are defined as above; R<34> and R<35> are independently hydrogen; R<28> is hydrogen, C1-4alkyl or C6-10ar(C1-4)alkyl; X' is O; n is from zero to 4; and m is zero to 2. 15. A compound of claim 14, wherein R<21> is phenyl. 16. A compound of claim 14, wherein R<25> is alkyl. 17. A compound of claim 16, wherein R<25> is methyl. 18. A compound of claim 1, wherein R<1> is phenyl, benzyl, 1-naphtylmethyl, 2-naphthylmethyl, pyridyl, quinolinyl or quinolinylmethyl, any of which is optionally substituted by 1-5 of chloro, methoxy, methyl, trifluoromethyl, cyano, nitro, methylsulfonyl, amino or dimethylamino. 19. A compound of claim 1, wherein R<1> is 8-quinolinyl, 5-chloro-2-thiophenylmethyl-8-quinolinyl, 8-quinolinylmethyl, 5-methyl-85-chloro-2-thiophenyl, 1-methyl-4-imidazolyl, pyridine, isoquinolinyl, pyridylmethyl or isoquinolinylmethyl. 20. A compound of claim 1, which is one of: 3-benzylsulfonylamino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2pyridinone; 3-(3-methylphenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone; 3-benzylsulfonylamino-6-methyl-1-[(1-(1-guanidinooxymethyl)cyclopropyl) aminocarbonylmethyl]-2-pyridinone; 3-(3-chlorobenzylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone; 3-(2-iodobenzylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone; 3-(2-chlorobenzylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone; 3-(2-bromobenzylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone; 3-(3-fluorobenzylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone; 3-(4-chlorobenzylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone; 3-(2-chloro-6-fluorobenzylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl) aminocarbonylmethyl]-2-pyridinone; 3-(2-fluorobenzylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone; 3-(4-fluorobenzylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone; 3-(2,3-dichlorobenzylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone; 3-(3,4-difluorobenzylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone; 3-(2,4-dichlorobenzylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone; 3-(2,5-dichlorobenzylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone; 3-(3,4-dichlorobenzylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone; 3-(1-naphthalenylmethylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl) aminocarbonylmethyl]-2-pyridinone; 3-(2-methylbenzylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone; 3-phenylsulfonylamino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2pyridinone; 3-(3-chlorophenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone; 3-(4-methoxyphenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone; 3-(3,4-dichlorophenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone; 3-(3-bromophenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone; 3-(3,4-dichlorophenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone; 3-(4-methylphenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone; 3-(4-ethylphenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone; 3-(3-methylphenylsulfonyl)amino-6-isopropyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone; 3-(3-methylphenylsulfonyl)amino-6-ethyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone; 3-(3-methylphenylsulfonyl)amino-6-propyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone; 3-(3-methylphenylsulfonyl)amino-6-methyl-1-[(2-N"-methylguanidinooxyethyl) aminocarbonylmethyl]-2-pyridinone; 3-(3-methylphenylsulfonyl) amino-6-methyl-1-[2-N"-butylguanidinooxyethyl) aminocarbonylmethyl]-2-pyridinone; 3-(3-methylphenylsulfonyl)amino-6-methyl-1-{[2-N"-(3-phenylpropyl)guanidinooxyethyl] aminocarbonylmethyl}-2-pyridinone; and pharmaceutically acceptable salts thereof. 21. A compound of claim 1, wherein said compound being present by 3-(3-methylphenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone or solvate, hydrate or pharmaceutically acceptable salt thereof. 22. A